Rheumatoid arthritis (RA) is a chronic inflammatory disease of uncertain etiology (1,2). Since the cause is unknown, treatment has been directed at suppressing the signs and symptoms of chronic inflammation. Although many agents have been documented to decrease pain and swelling temporarily, none has been shown to have a major impact on the course of the disease. New therapeutic modalities have been developed over the past few years, employing monoclonal antibodies, cytokine antagonists, specific receptor targeted toxins, and other biologics (3-17). Nevertheless, uniform and persistent suppression of disease activity has not been reported. Although these approaches remain promising, alternative means of drug development seen warranted and could yield not only new and effective treatment modalities, but also provide new insights into disease pathogenesis that could serve as the basis of future therapeutic innovations.
An area to search for new therapeutic interventions for RA is that of traditional Chinese medicines. One of these traditional medicines is from Tripterygium wilfordii Hook F, a shrub-like vine from the Celastraceae family (18). A variety of preparations derived from this plant have been used in South China for many years to treat different forms of arthritis and other autoinmune diseases. In 1978, an extract of Tripterygium wilfordii Hook F was produced by chloroform reethanol extraction of the woody portion of the roots and designated T2 (18). Reports in the Chinese literature describe T2 treatment of more than 750 patients with a variety of autoimmune diseases (19-35). The general impression has been that T2 is well-absorbed orally, appears to have acceptable toxicity, and is effective in the treatment of various autoimmune diseases.
T2 was evaluated in a double-blind placebo controlled cross-over study involving 70 RA patients, with a mean disease duration of 6 years (19-20). Statistically significant improvement in all clinical parameters, particularly ESR, CRP, and Rheumatoid factor titers, was noted after 12 weeks of therapy in the experimental group compared with either baseline measurements or the placebo treated group. Of the patients treated, 82-93% noted improvement in different clinical criteria or laboratory correlates of inflammation. An immunosuppressive activity was implicated by the finding that treatment induced inhibition of the production of IgM and IgM rheumatoid factor by the patients' peripheral blood mononuclear cells in vitro (20). Toxicity, which consisted primarily of skin rash, gastrointestinal complaints and amenorrhea, was generally mild and reversible with cessation of therapy. These results support the contention that T2 might be an effective therapy for RA, but there is little experience with this agent outside of China.
Tripterygium wilfordii Hook F is known to contain a number of constituents, some of which appear to be toxic (36). It is known that the leaves, stem, flowers, and the skin of the roots are poisonous and that ingestion can cause death (37-39). In contrast, the woody portion of the roots of the plant is much less toxic. T2 is prepared from the woody portion of the roots, appears to contain the therapeutic components, and to have reduced toxicity compared with other preparations.
The Chinese experience has suggested that a daily dosage of 0.8-1.5 mg/kg of T2 is safe and effective. Acute and chronic toxicity studies have been carried out in China using a variety of animal models. The LD.sub.50 in mice is 159.7.+-.14.3 mg/kg (40). The major chronic toxicity noted in rats administered 30 mg/kg for 90 days was azoospermia and decrease in testicular weight (40). Lower dosages of T2 did not cause decreases in testicular weight. The toxicity studies, therefore, suggest that T2 exhibits a reasonable safety index and should be able to be administered to patients safely.
Research has begun in China to determine the spectrum of activity of T2. Triptonide and triptolide from this plant have been reported to inhibit the proliferation of lymph cells induced by concanavalin A. ((Zhang et al., Shanghai Yike Da ue Xuebao, 1986, 13 (4) pp. 267-272.)) Additionally, ancient Chinese medical books have suggested that this herbal remedy is useful to treat joint pain. Recently, this extract has been used in the treatment of rheumatic diseases including rheumatoid arthritis, as well as systemic lupus erythematosus, Behcet's disease, and psoriasis. Alcoholic extracts (T2) of the plant have been described as having significant activity in vivo against certain mouse leukemias and in vitro against cells derived from human carcinomas (Kupchan et al., J. An. Chem. Soc., 1972, 94 pp. 3194-3195). The capacity of T2 to suppress a number of animal models of autoinmune disease, including adjuvant arthritis and experimental allergic encephalomyelitis, has been reported (41-47). Large concentrations of T2 (30 mg/kg) suppress delayed hypersensitivity reactivity in mice and may also suppress graft versus host disease, as well as skin and heart allograft rejection (36,41). In general, however, only very large concentrations of T2 have been examined in these studies. It, therefore, remains unclear whether lower, more pharmacologically appropriate concentrations would also exert therapeutic effects in these animal models.
T2 is a crude extract containing a mixture of materials, including various glycosides, alkaloids, and diterpenoids. The active principle, however, has not yet been identified. A few components have been purified, including triptolide, wilfordine, and related compounds, but proof that a particular purified component accounts for the therapeutic or immunosuppressive activity of T2 does not exist (48).
High concentrations of triptolide were reported to suppress B and T lymphocyte proliferation and interleukin-2 production by mouse spleen cells (Pu et al. (1990) Chem. Abstracts, 112:45, abstract 171972d). The concentrations used were sufficiently high that significant nonspecific toxicity undoubtedly occurred.